Shared Genetic Liability and Causal Associations Between Major Depressive Disorder and Cardiovascular Diseases

Abstract

Major depressive disorder (MDD) is phenotypically associated with cardiovascular diseases (CVD). We aim to investigate mechanisms underlying relationships between MDD and CVD in the context of shared genetic variations. Polygenic overlap analysis was used to test genetic correlation and to analyze shared genetic variations between MDD and seven cardiovascular outcomes (coronary artery disease (CAD), heart failure, atrial fibrillation, stroke, systolic blood pressure, diastolic blood pressure, and pulse pressure measurement). Mendelian randomization analysis was used to uncover causal relationships between MDD and cardiovascular traits. By cross-trait meta-analysis, we identified a set of genomic loci shared between the traits of MDD and stroke. Putative causal genes for MDD and stroke were prioritized by fine-mapping of transcriptome-wide associations. Polygenic overlap analysis pointed toward substantial genetic variation overlap between MDD and CVD. Mendelian randomization analysis indicated that genetic liability to MDD has a causal effect on CAD and stroke. Comparison of genome-wide genes shared by MDD and CVD suggests 20q12 as a pleiotropic region conferring risk for both MDD and CVD. Cross-trait meta-analyses and fine-mapping of transcriptome-wide association signals identified novel risk genes for MDD and stroke, including RPL31P12, BORSC7, PNPT11, and PGF. Many genetic variations associated with MDD and CVD outcomes are shared, thus, pointing that genetic liability to MDD may also confer risk for stroke and CAD. Presented results shed light on mechanistic connections between MDD and CVD phenotypes.

Keywords: Mendelian randomization; cardiovascular disease; major depressive disorder; polygenic overlap; stroke.

Figure 1

Shared causal variants and causal effects between MDD and CVD. MDD, major depressive disorder; HF, heart failure; AF, atrial fibrillation; CAD, coronary artery disease. (A) Venn diagrams of unique and shared causal variants between major depressive disorder and cardiovascular diseases. The numbers indicate the estimated quantity of causal variants (in thousands) per component, explaining 90% of SNP heritability in each phenotype. The size of the circles reflects the degree of polygenicity. (B) Causal effects of MDD on cardiovascular diseases. The dotted lines denote effect sizes (b_xy). (C) Overlapped genes between major depressive disorder and cardiovascular disease from GWAS-catalog. The matrix of solid and empty circles at the bottom illustrates the “presence” (solid green) or “absence” (empty) of the gene sets in each intersection. The numbers to the right of the matrix are set sizes. The colored bars on the top of the matrix represent the intersection sizes with the color intensity showing the P-value significance. (D) Pleiotropic genes shared by MDD and CVD. (E) Mechanisms underlying associations between MDD and CVD. (F) Gene property analysis for tissue specificity in general GTEx tissues. (G) Fine-mapping of TWAS hits within 14:72890537-14:76444767 in heart_left_ventricle. Transcriptome-wide association signal indicating the strength of predicted expression associated with the trait.

Figure 2

Meta-analysis of major depressive disorder with stroke. (A) Manhattan plot of the meta-analysis. The x-axis is the chromosomal position of SNPs and the y-axis is the significance of the SNPs (-log₁₀P). Genes implicated by independent significant SNPs were annotated. (B–D) The four highlighted genomic loci. Each SNP is color-coded based on the highest r² to one of the independent significant SNPs if that is greater or equal to the r² threshold of 0.6. Other SNPs (below the r² of 0.6) are colored in gray.